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Title: Polyethyleneimine as an adjuvant candidate for Env-based HIV-1 immunisation
Author: Brinckmann, Sarah Anna
ISNI:       0000 0004 2727 7368
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2012
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Almost 30 years after the identification of HIV-1 as the causative agent of AIDS, an effective prophylactic HIV-1 vaccine has yet to be developed. Despite the design of a vast array of therapeutic agents and prevention strategies, which have helped to reduce AIDS mortality and the growth of the pandemic, HIV-1 is still the fourth biggest killer worldwide and an effective vaccine will be needed to halt the pandemic. Over the past three decades, various HIV-1 vaccination strategies have been explored leading to the key understanding that sterile protection against HIV-1 infection will require a combination of cellular and humoral responses, particularly at the mucosal compartment, the common route of infection. Consequently, it has been postulated that this can only be achieved through a potent and effective immunisation strategy involving mucosal immunisation and the application of a heterologous prime-boost regimen. However, the mucosal route of immunisation, in particular for subunit vaccines, has not been well established as a mainstream mode of vaccination in human and results with experimental mucosal immunisation have generally been impeded by a lack of safe and effective mucosal adjuvants. In the work presented herein, I investigated whether the highly cationic polyethyleneimine (PEI), a gold standard DNA delivery agent, has adjuvant activity applied parenterally and mucosally in formulation with glycoprotein antigens, in particular HIV-1 Env gp140, the sole target of neutralising antibodies (nAbs) and therefore the most attractive HIV-1 subunit vaccine candidate. I demonstrated that PEI is a potent inducer of Env-specific Ab responses in a mixed Th1 and Th2 context. PEI is particularly potent via the mucosal route and superior to gold standard mucosal adjuvant Cholera Toxin Beta subunit (CTB) as measured by HIV-1 specific IgA responses at the mucosal compartment. PEI showed direct immune stimulatory effects, marked by a significant recruitment of local leukocytes, including inflammatory monocytes and dendritic cells (DCs). Further it associated with antigen to form gp140-PEI particles, which enhanced antigen targeting to, and uptake by, immune cells, in particular monocytes, macrophages, and DCs. The observed adjuvant activity was maintained with the use of various forms of PEI, including linear or branched, and durable or biodegradable, and under a range in molecular weight (MW), suggesting that immune potentiation is a shared attribute of this group of PEI polymers. This is the first demonstration of PEI as a mucosal adjuvant for protein immunisation. These results merit further exploration of PEI in protection models with the implication for clinical trials.
Supervisor: Sattentau, Q. J. ; Wegmann, F. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medical Sciences